Dermal or transdermal therapeutic system comprising an ormocer with barrier effect on a cover foil

ABSTRACT

The invention relates to a dermal or transdermal therapeutic system comprising a cover foil with barrier effect against gas, odour and volatile light substances. Said invention is characterised in that the cover foil is provided with at least one substrate and with at least one layer consisting of an inorganic-organic hybrid polymer (Ormocer).

The present invention relates to a dermal or transdermal therapeuticsystem comprising a covering film having a barrier effect against gases,aromas and readily volatile substances, which system is characterized inthat the covering film is composed of at least one supporting layer anda layer composed of an inorganic-organic hybrid polymer (ormocer).

Dermal therapeutic systems are systems which bring a pharmaceutical,topically acting substance into contact with the affected skin segmentor the affected musculature which lies below it; all so-called medicinalplasters belong to this category. Transdermal therapeutic systems, onthe other hand, convey the active compound through the skin into theblood circulation and consequently act systemically. Both systems areessentially composed of a covering film (backing layer), an activecompound reservoir or an active compound-containing matrix and aprotective film which can be peeled off (release liner). The coveringfilm remains on the dermal or transdermal therapeutic system during theapplication as well in order, on the one hand, to mechanically protectthe active compound-containing matrix or the active compound-containingreservoir and, on the other hand, either to protect the active compoundfrom the influence of gases, e.g. oxygen and water vapor, or to preventthe partial evaporation of a readily volatile active compound.

Both the covering film, which serves as backing layer, and the peelableprotective film are generally composed of organic polymers. Examples ofsuitable materials for these films are: low density polyethylene (LDPE)and high density polyethylene (HDPE), polypropylene (PP), polyamide(PA), polyvinyl chloride (PVC), polyvinyl ester, polyethyleneterephthalate (PET), copolymers composed of at least two of thesepolymers, or mixtures of these polymers. Since the covering film remainson the skin during the use of the system, it should be as flexible andelastic as possible in order to ensure appropriate comfort when beingworn by the patient. Inflexible films lead to the formation of folds andto the skin being cut into. LDPE and HDPE, in particular, form suitableflexible and elastic covering films. However, all the abovementionedpolymers, and, in particular, the two polyethylenes, suffer from thedisadvantage that, to differing extents, they constitute good storagesystems for active compounds. As a result, there is the danger that,during storage and/or use, the active compound may migrate out of thereservoir or the active compound-containing matrix and, by way of thegas space, into the covering film until the saturation concentration isreached. This thereby minimizes the active compound which is availablein the matrix or the reservoir for permeation through the skin andminimizes the release kinetics of the dermal or transdermal therapeuticsystem.

DE 199 22 368A1 describes polymer compositions composed of water-solublepolymers and bound silicon dioxide building blocks, which are linked bypolymerization, as material for pharmaceutical supporting materials.However, these compositions do not correspond to that of the ormocers.

DE 195 19 593 describes a transdermal therapeutic system for the releaseof volatile active compounds, which system comprises a backing layerwhich is essentially impermeable for the active compound and which iscomposed of a thermoplastic organic polymer.

WO 95/07817 describes a multilayer film which is impermeable for oxygenand moisture and which is produced by extraction from nylon and/orcopolymers composed of ethylene and vinyl alcohol together with athermoplastic organic polymer.

DE 199 58 554 A discloses a transdermal therapeutic system whichcomprises a backing layer which is impermeable for active compounds, atleast one polymer layer, having microreservoirs which are containedtherein, and at least one active compound and a protective layer whichis to be removed prior to use. The material of the backing layer iscomposed of films such as polyethylene, polypropylene or polyester or oflaminates of different polymers.

Amberg-Schwab S. et al: “Inorganic-organic polymers as migrationbarriers against liquid and volatile compounds”, Journal of Sol-GelScience and Technology 26, 699-703, 2003. The publication describes theinvestigation of different, photochemically curable hybrid polymers,which are synthesized on the basis of the sol-gel technique, as a novelcoating material for use as migration barriers having good propertieswith regard to printability, abrasion resistance and antistatics for thepackaging industry.

WO 02/34510 A1 discloses a flexible sterile-goods packaging materialwhich is composed of a film or a film composite having barrierproperties towards gases, water vapor and aromas and which comprises asupporting film and, arranged on this, a thin ceramic layer onto which afunctional layer composed of an inorganic-organic hybrid polymer is inturn applied. The material is suitable for sterilizing at hightemperatures.

Knittel D. et al: “Surface of Textiles and the Human Skin: 1. SurfaceModification of Fibers as Therapeutic and Diagnostic Systems”, ExogenousDermatology 2003; 2, 11-16. The publication describes a new method forimproving the skin-facing surfaces of textiles with cyclodextrins byanchoring them on the textile surface. In addition it is proposed thatthe textiles be functionalized with active compound-containing,inorganic-organic hybrid systems which are to serve as depots forcontrolled release.

It has furthermore already been proposed to reduce or completely preventthe permeability of flexible or elastic polymer layers for gases orvolatile active compounds by combining polymers with metal layers, e.g.by means of a coating with aluminum or else by means of coating withmetal oxides. Unfortunately, however, such a combination markedlyimpairs the flexibility, but in particular the elasticity, of thesesystems.

The object of the present invention is therefore to develop dermal ortransdermal therapeutic systems having covering films which possess goodflexibility and, at the same time, an outstanding barrier effect withregard to readily volatile active compounds or active compounds having ahigh vapor pressure.

According to the invention, this object is achieved by using coveringfilms which are composed of organic polymers which are coated with aninorganic-organic hybrid polymer, i.e. what is termed ormocer.

Inorganic-organic hybrid polymers, i.e. what are termed ormocers, havebeen known for some years. They are prepared in two steps in thefollowing manner: initially, an inorganic network is synthesized by thecontrolled hydrolysis and condensation of organically modified siliconoxides, with a cocondensation with other metal alkoxides (Ti, Zr and Alalkoxides) also being possible. In a second step, the polymerizablegroups which are linked to the inorganic network then react with eachother as a consequence of thermal or UW treatment. Such a hybrid polymerthen possesses the structural formula which is shown diagrammatically inFIG. 1.

The preparation and properties of ormocers have been described in thefollowing publications: EP 0 358 011 A2; EP 0 373 451 A1; EP 0 610 831A2; EP 0 644 908 B1; EP 0 792 846 A1; EP 0 934 989 A These publicationsare mentioned here expressly as being part of the disclosure.

Whereas it has not previously been possible to produce covering films,for dermal or transdermal systems, which possess good barrier propertiesand, at the same time, satisfactory elastic properties, it has now beenfound, surprisingly, that coating polymer films with ormocers, whosegood barrier effect is already known, leads to covering films whoseelasticity is either unimpaired or only insignificantly impaired.Ormocer layers having a thickness of between 1 μm and 10 μm areparticularly suitable.

Both the covering film, which serves as backing layer, and the peelableprotective film are generally preferably composed of organic polymers.Examples of suitable materials for these films are: low densitypolyethylene (LDPE) and high density polyethylene (HDPE), polypropylene(PP), polyamide (PA), polyvinyl chloride (PVC), polyvinyl ester,polyester polyethylene terephthalate (PET), copolymers composed of atleast two of these polymers, or mixtures of these polymers. Since thecovering film remains on the skin during the use of the system, itshould be as flexible and elastic as possible in order to ensureappropriate comfort when being worn by the patient. Inflexible filmslead to the formation of folds and to the skin being cut into. LDPE andHDPE, in particular, form suitable flexible and elastic covering films.

In order to investigate the suitability of ormocer-coated flexiblecovering films, an HDPE film of a thickness of 175 μm was coated with anormocer lacquer of the abovementioned composition. The films, which werecoated on both sides, were introduced into a gas space containingnicotine and the uptake of active compound by the films after 4 and 8weeks of incubation at 40° C. was determined. The results of theinvestigations are shown in FIG. 2.

It was likewise possible to demonstrate that the covering filmsaccording to the invention possess good extensibility, that isconsequently possess elasticity, and that the barrier properties arealso preserved in the extended state. In order to show this, an HDPEfilm which was coated with the hybrid polymer ormocer was extended by 3%and the uptake of active compound after 4 and 8 weeks of exposure tonicotine was determined. The results are depicted in FIG. 3.

1. A dermal or transdermal therapeutic system comprising a peelableprotective layer, a reservoir or matrix layer containing at least oneactive compound and a covering film having a barrier effect againstgases, aromas and readily volatile substances, characterized in that thecovering film is composed of at least one supporting layer and at leastone layer composed of an ormocer.
 2. The dermal or transdermaltherapeutic system as claimed in claim 1, characterized in that theormocer is obtained by the hydrolytic condensation of organicallymodified silicon dioxides.
 3. The dermal or transdermal therapeuticsystem as claimed in claim 1, characterized in that the supporting layeris composed of at least one organic polymer.
 4. The dermal ortransdermal therapeutic system as claimed in claim 3, characterized inthat the organic polymer is composed of low density or high densitypolyethylene, or of polypropylene, polyamide, polyvinyl chloride,polyvinyl ester or polyester, of a mixture of at least two of thesepolymers or of at least one copolymer composed of at least two monomersof the abovementioned polymers.
 5. The dermal or transdermal therapeuticsystem as claimed in claim 1, characterized in that the supporting layeris composed of polyethylene terephthalate.
 6. The dermal or transdermaltherapeutic system as claimed in claim 1, characterized in that theormocer layer has a thickness of between 1 μm and 10 μm.
 7. The dermalor transdermal therapeutic system as claimed in claim 1, characterizedin that the ormocer layer is applied on the supporting layer such thatit is adjacent to the active compound-containing layer.
 8. The dermal ortransdermal therapeutic system as claimed in claim 1, characterized inthat in each case at least one ormocer layer is applied on both surfacesof the supporting layer.
 9. The dermal or transdermal therapeutic systemas claimed in claim 1, characterized in that it comprises a readilyvolatile active compound.
 10. The dermal or transdermal therapeuticsystem as claimed in claim 9, characterized in that the active compoundis nicotine.